The Quest for Life

Northwestern scientists, doctors and engineers collaborate across disciplines in their efforts to diagnose diseases earlier, cure cancer and even regenerate damaged nerves in broken spinal cords.

by Megan Fellman

It was a cold afternoon in January 2001.

“I got the phone call that every parent dreads getting,” says John Kessler.

A neurosurgeon at Hartford Hospital in Connecticut — not far from where Kessler’s daughter Allison was attending prep school — was on the other end of the line.

After questioning his fellow neurologist, Kessler, the Ken and Ruth Davee Professor of Stem Cell Biology and chair of the department of neurology at the Feinberg School of Medicine, knew that his daughter, then 15, would likely not walk again. Allison had suffered an accident while downhill skiing that left her paralyzed from the waist down, with virtually no function. A dislocated vertebra in her lower back had crushed her spinal cord.

At the time of Allison’s injury, Kessler’s research centered on regenerating the nervous system in relation to peripheral nerve disorders. Now he has a new goal.

“I want to help people walk again,” says Kessler, who is also director of the Frances Evelyn Feinberg Clinical Neuroscience Research Institute.

So he turned to Samuel Stupp (GMcC77), Board of Trustees Professor of Materials Science, Chemistry and Medicine and director of Northwestern’s Institute for BioNanotechnology in Medicine, who was developing some interesting new materials that might be useful in healing human tissue.

Could the technology help regenerate nerves in the spinal cord?

Investing in the Future

Science is all about doing things that no one has ever done before.

And solving the complex problems found in medicine — such as spinal cord repair, Alzheimer’s disease, cancer, diabetes and cardiovascular disease, to name just a few — cannot be done by a scientist alone in the lab.

Today, with the explosion of biological information coming from the Human Genome Project, the related study of proteins (proteomics) and powerful new instrumentation, biologists and physicians are not the only life scientists anymore. Engineers, materials scientists, physicists, computer scientists and chemists are life scientists, too.

Real innovation in the biomedical sciences, the kind that will have the greatest impact on society and human health, will spring from collaborative teams that meld different areas of expertise and viewpoints. The National Institutes of Health — the nation’s primary source of biomedical research funding — has recognized this with a new emphasis on interdisciplinary research, in addition to basic science.

This focus plays to Northwestern’s strengths: a strong culture of collaboration, state-of-the-art research facilities that are some of the best in the country, top faculty who are driven to be pioneers, administrative leaders committed to the life and biomedical sciences, a large array of schools and programs, and a history of inventing new interdisciplinary academic fields.

For the past decade, much has happened at the Feinberg School and on the Evanston campus to make a university already strong in the biomedical sciences even stronger.

“When I came here in 1995, I very much had in my mind that advancing the University would depend on investing heavily in biomedical research,” says President Henry S. Bienen. “Investments in facilities on both campuses were a precondition for doing anything else. Fortunately, we had donors who shared that vision. Space was a necessary but not sufficient condition for moving ahead. We had diverse research strengths we could build on. We have been able to leverage the medical school and the life sciences, including engineering, and increase collaboration between our campuses. And I think those bets have paid off.”

Since 1999 Northwestern has made an enormous investment in new buildings and renovations that encourage interaction, innovation and cross-disciplinary teams and provide shared research facilities and resources. (See “Facilities Are Foundation for Collaboration.”)

“Northwestern is this fascinating place that has distinguished itself by creating the culture, environment and incentives to gather together interesting arrays of ideas and pick out really big challenges,” says Provost Lawrence B. Dumas. “For reasons of history, accident and design, Northwestern has proven to be a place where it’s easier to do collective work than other places. And the layout of physical space has turned out to have a huge impact on the culture of collaboration.”

This has enabled the University to attract excellent new faculty, as well as retain the physicians, scientists and engineers already here. Feinberg has hired 140 new tenured and tenure-track faculty in the last six years alone. New research teams with faculty from both campuses have been awarded large competitive grants to address important health care problems. And collaborations have grown not only at the University but also between Northwestern and its affiliated teaching hospitals and with other Chicago institutions.

The goal of this enterprise, in addition to the educational component, is to transform medicine — through a fundamental understanding of the molecular and cellular processes of disease, through the discovery of new targets for therapeutics, through innovative new technologies that regenerate organs or detect cancer earlier and through the human clinical trials that determine if a treatment or technique works — and to bring these discoveries to the individuals who need them.

The Frontier of Regenerative Medicine

The new labs at the Institute for BioNanotechnology in Medicine in the Robert H. Lurie Medical Research Center, as well as labs in the Montgomery Ward Memorial Building, are where Jack Kessler and Sam Stupp and their research groups are working on regenerating the spinal cord, with the hope that one day people like Allison Kessler can walk again.

Kessler and Stupp (see “Crossing Borders,” spring 2001) know that tackling this problem and others in the field of regenerative medicine — where the goal is regrowth of tissues and organs — requires the marriage of medicine with technology, which is why they make such a powerful team.

“Neurons don’t regenerate spontaneously,” says Stupp, “and we are using nanostructures to reconstruct the three-dimensional extracellular matrix that mimics the cell’s environment. Matrices deliver important signals to cells to induce their proliferation and differentiation into specific tissues and organs.”

At IBNAM a group of materials scientists and chemists design and make the nanoscale materials that become the extracellular matrices. When the materials are injected as a gel into tissue, they self-assemble into the synthetic matrices necessary for promoting neuron growth. (The materials can be injected with or without stem cells.) The biological work is done in Kessler’s labs in the Ward building.

Kessler and Stupp have some promising results. They demonstrated that their approach can regenerate old nerve connections in rats with spinal cord injuries, restoring some function. The goal, says Kessler, is to take the technology to human clinical studies, which they expect will begin within two years.

“In medicine we now are able to treat symptoms and prevent disease, but the one thing that hasn’t happened yet is regenerative medicine,” says Kessler, who uses neural stem cells and embryonic stem cells in his spinal cord research. “Regenerating organs that have been damaged will be the next big change in medicine.”

Kessler’s and Stupp’s research is supported by a major Bioengineering Research Partnership grant to IBNAM from NIH that brings together seven investigators from both campuses who are working on regenerative matrix and scaffold technologies for the central nervous system and diabetes — technologies that Stupp says are essential if regenerative medicine is to succeed.

Two of these researchers — Dixon Kaufman, a transplant surgeon and professor and vice chair for research in the department of surgery, and William Lowe, professor of endocrinology and vice chair for research in the department of medicine — are leading experts on diabetes. “Pancreas and islet cell transplantation has been used successfully to treat individuals with type 1 diabetes,” says Kaufman, “but problems such as the donor shortage, in this case the pancreas and islets, currently limit the number of people who can be treated.”

The physicians are working with Stupp and other bioengineers to see if their extracellular matrices could one day be used to deliver and increase the survival of transplanted islet cells implanted into patients with type 1 diabetes who have lost the ability to make insulin. The goal is to cure these individuals of diabetes by implanting a new supply of insulin-producing islets. The researchers also are investigating alternative sites for islet implantation, such as in the abdomen or under the skin. (Islet cells are now implanted in the liver.)

“These collaborations will accelerate our research and translate our findings to humans more quickly,” says Lowe. “We are fortunate here at Northwestern to be able to attack biomedical problems from a variety of angles.”

The multiple technologies being developed by the dozen or so researchers working at the University in regenerative medicine are fairly generic, increasing the likelihood that they can be used for other medical problems, including cardiovascular and orthopedic applications. Stupp is already working with Jon Lomasney, assistant professor of pathology and molecular pharmacology and biological chemistry, Nirat Beohar (GFSM99), assistant professor of cardiology, and Charles Davidson (GFSM85), professor of cardiology, to develop strategies to regenerate heart tissue after infarction.

Taking on Cancer

“This is a very competitive time in biomedical research,” says C. Bradley Moore, vice president for research. “The NIH budget doubled over a five-year period that ended in 2003, and universities across the country made huge investments in medical research facilities. There is not enough money for everyone. With the budget fixed since 2003, we now have to compete much better than our peers, and that’s not easy.”

Northwestern has fared well in this competitive climate. Total sponsored research awards (from federal and nonfederal sources) have steadily climbed in recent years to $383.8 million in 2006, more than doubling the award dollars since 1995.

A recent funding success was Northwestern’s combining its leadership in both cancer biology research and nanotechnology to secure a significant grant from the National Cancer Institute to establish a Center for Cancer Nanotechnology Excellence, one of only seven in the country. Chad Mirkin, George B. Rathmann Professor of Chemistry and director of Northwestern’s International Institute for Nanotechnology, directs the center, with leadership also provided by Steven Rosen (FSM72, 76, GFSM79, 81), director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Teams of scientists, engineers and clinicians will build on previous discoveries to develop innovative nanotechnology approaches and devices to combat cancer. Jill Pelling (WCAS74), associate director of the new center, associate director for translational research at the Lurie Cancer Center and professor of pathology, will facilitate investigator interactions between the two campuses.

Some initial projects include developing highly sensitive and selective nanoscale sensors for the early detection of ovarian cancer and combining advances in molecular and cell biology with nanotechnology to develop a new class of drugs that inhibit cancer cells from spreading.

The Lurie Cancer Center is the only comprehensive cancer center in Illinois, as designated by the National Cancer Institute. Patient care and research are its cornerstones. Physicians treat between 15,000 and 20,000 new cancer patients each year; center researchers study the causes and behavior of cancer with the goal of improving cancer treatment and prevention.

“All breakthroughs for patient care are a result of scientific ingenuity that leads to clinical treatments,” says Rosen, Genevieve E. Teuton Professor of Medicine, who recently developed new compounds for treating leukemia and other blood cancers. “The advances we are witnessing now are proceeding at a much more rapid pace, although we are still dealing with mortality.”

One of the most profound changes he has witnessed is the ability to prolong the lives of patients through targeted therapy. Rosen has had a number of “miracle patients” who have lived longer and more productive lives because they responded well to new medications that didn’t even exist a few years ago.

The ability to detect cancer early, long before symptoms appear, represents a supreme challenge. Thomas Meade, Eileen M. Foell Professor in Cancer Research and professor of chemistry, biochemistry, molecular biology and cell biology, neurobiology and physiology and radiology, wants to create molecules that are both diagnostic and therapeutic tools.

Meade has invented “smart dyes” for in vivo imaging — custom-designed molecules that may detect cancer cells about to go metastatic. The dye looks for a single biochemical signature associated with the abnormal cells, such as the presence of a particular enzyme, and lights up when the enzyme is detected. The molecular event is imaged by magnetic resonance imaging. Eventually Meade would like to develop smart dyes that include a therapeutic component, simultaneously triggering drug delivery after the dangerous cells are detected.

He also is working with a number of physicians at the Feinberg School, including Kaufman and Kessler, who want to use another of his inventions for imaging — fate-mapping agents. These contrast agents are used to label cells, such as beta islet cells or stem cells, and track them in an animal over time.

“I have many collaborations going at Feinberg, and most of them are because of Dr. Rosen,” says Meade, a Lurie Cancer Center member who oversees a large interdisciplinary research team. “Steve is always making connections and facilitating the translation of research. I have never been so challenged in so many ways as I have been at Northwestern.”

Current life-saving cancer treatments, such as chemotherapy, often have the serious side effect of destroying the reproductive potential of women and girls. New technology being developed at Northwestern could lead to the creation of egg banks and help these women eventually have their own biological children.

Teresa Woodruff (G89), Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology, and Lonnie Shea, associate professor of chemical and biological engineering, are working with Ralph Kazer, professor of obstetrics and gynecology and an infertility specialist, to develop strategies to provide the synthetic environment needed to support the egg maturation process.

Mature eggs that are frozen cannot be used for fertility treatments because they are destroyed in the freezing process, explains Woodruff. Immature eggs can be frozen, but they need an artificial environment that allows them to mature to the point where they can be fertilized successfully.

Responding to these problems, Shea has developed a technology that mimics the ovary and its environment. The three-dimensional biomaterial, called alginate, maintains normal connections between follicle and egg, enabling the eggs to develop. In recent animal studies Woodruff and Shea have shown that eggs matured with their method can be fertilized and ultimately lead to healthy embryos and the birth of live mice. Currently the group is working with dog, cat, sheep and monkey ovaries in an attempt to bridge the gap between bench and bedside.

“While the research is in its early stages, this work has implications for the preservation of fertility for women and girls with cancer,” says Woodruff, who is director of the basic science program at the Lurie Cancer Center. The center has established a program in oncofertility to provide options for women struggling with a cancer diagnosis and the potential loss of fertility.

Other Critical Research Areas

Northwestern has many other strengths on which it is building, including research in the areas of genetics, sleep and circadian biology, neurodegenerative disease and the impact of social inequality on human health.

“Genetics is the information technology system of the life sciences and is a key component of biomedical research at Northwestern,” says Rex Chisholm, director of the Center for Genetic Medicine and Adam and Richard T. Lind Professor of Medical Genetics. “The most complex and common diseases are caused by interactions between multiple genes and the environment.”

To better understand the role genes play in the development and treatment of diseases, the center is spearheading an important interdisciplinary research initiative called NUgene, now in its fourth year. One of the first of its kind in the country, NUgene is a major gene banking study with the goal of enrolling 100,000 people by 2010.

NUgene collects and stores DNA samples and associated health information from patients at Northwestern-affiliated hospitals and clinics. The clinical information and DNA can be used by researchers at Northwestern and across the country to search out “candidate genes” believed to play a role in disease, ascertain their role in the disease process and determine which therapies would be most effective.

“Our ability to look at patterns across the entire genome and apply the information to human disease is relatively new,” says Chisholm. “Some of the early hits from this approach will be in the area of personalized medicine — learning who will respond to a particular drug and who won’t.”

Defects in genes play a major role in neurodegenerative diseases, but exactly how the mutations lead to the degeneration of nerve cells is unknown. Richard Morimoto, Bill and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell Biology, is trying to unlock these mysteries. In studies using genes found in Huntington’s disease and inherited forms of amyotrophic lateral sclerosis, he has made progress in understanding how the mutated genes affect protein folding and protein degradation and how the processes cause cell death and initiate the events that lead to cell death. His findings have implications for other neurodegenerative diseases.

Alzheimer’s disease, which strikes one in 10 people past the age of 65 and nearly half over 85, is another research focus at Northwestern. In a breakthrough in understanding the disease, William Klein, professor of neurobiology and physiology, and his colleagues have discovered a new neurotoxin that builds up to high levels in the brains of Alzheimer’s patients. Known as an ADDL, this toxin causes dementia by attacking the brain’s synapses where memory formation begins.

“We’re now at the forefront of an international effort to understand why ADDLs accumulate and how they damage the memory process,” says Klein, a member of Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center. “It’s very likely that the first effective treatment for Alzheimer’s will come from new types of drugs or vaccines that eliminate ADDLs from the brain.”

Sleep disorders are common and often associated with impairments of physical and mental functions. However, little is known about the mechanisms behind the problems.

Researchers at Northwestern are conducting both basic science and clinical research studies to learn more about the genetics and physiology of sleep and circadian rhythm disorders. (Sleep is one of the rhythms that the circadian clock controls.)

“We know that a short sleep duration of less than seven hours increases the risk of obesity, diabetes and cardiovascular disease, but we don’t know why,” says Phyllis Zee (GFSM87, 89), professor of neurology and director of the Sleep Disorders Center at Northwestern Memorial Hospital. “Sleep — which is as important as exercise and nutrition — now is being seen as more relevant to all areas of medicine.”

Zee, associate director of Northwestern’s Center for Sleep and Circadian Biology, directs a range of clinical studies on the Chicago campus, including one focused on the genetics and treatment of circadian rhythm sleep disorders and another looking at the effects of aerobic exercise on the sleep and health measures in older individuals with chronic insomnia. She is particularly interested in how aging alters circadian and sleep function.

Some of the first evidence linking a faulty body clock to poor physical health came out of a basic science study last year led by Fred Turek, circadian rhythm expert and Charles E. and Emma H. Morrison Professor of Biology, and Joe Bass, assistant professor of medicine at Feinberg and head of the division of endocrinology and metabolism at Evanston Northwestern Healthcare.

They showed that if the 24-hour internal clock, which regulates both sleep and hunger, is faulty or misaligned, it can wreak havoc on the body and its metabolism, increasing the propensity for obesity and diabetes.

“Our findings lead to provocative questions that require further investigation,” says Bass, who has a lab in the Arthur and Gladys Pancoe–Evanston Northwestern Healthcare Life Sciences Pavilion. “Is it possible that sleep loss or a change in circadian rhythms might exacerbate problems in regulating appetite? Are you eating at a time of day when your system is internally aligned to optimally metabolize food?”

Of course, diabetes is not just a problem of understanding the circadian clock or islet cells. It is a societal problem as well. Cells to Society, a new center funded by NIH and part of Northwestern’s Institute for Policy Research, is bringing social scientists together with biomedical researchers to better understand the relationship between social inequality and health. Researchers are focusing on how stress associated with poverty and discrimination, for example, affects brain and body chemistry and may lead to health problems, such as cardiovascular disease and diabetes.

“We expect C2S research to influence policy and practice agendas and ultimately reduce some of the challenging health disparities that children and adults face throughout their lives,” says center director Lindsay Chase-Lansdale, professor of human development and social policy.

Moving Northwestern and Chicago Forward

With collaboration and innovation essential to securing funding, advancing scientific research and translating results to patient care, Northwestern has worked hard to forge partnerships outside of the University. The new endeavors promise to strengthen biomedical research and education at Northwestern and throughout the entire Chicago area.

Malfunctioning proteins are the root cause of many diseases, and a better understanding of them could lead to new drugs or other treatments to cure or control disease. The Chicago Biomedical Consortium brings scientists from Northwestern, the University of Chicago and the University of Illinois at Chicago together to study the role proteins play in illness and health. The basic science discoveries that emerge from research partnerships will be included in a database about proteins — available to anyone, including physicians, scientists and industry.

“Through the CBC we want to make the Chicago area an exciting place to do path-breaking biomedical science,” says Rick Morimoto, Northwestern’s CBC liaison. “Our goal is to change the entire way research, education and training are done at three great universities by creating a vibrant community of researchers who look to their CBC colleagues for collaborative opportunities.”

Another important resource for biomedical researchers is Argonne National Laboratory, located just west of Chicago, which offers specialized facilities that no university could operate alone. The extremely brilliant X-rays produced by the Advanced Photon Source synchrotron, for example, allow researchers to determine the three-dimensional structure of proteins.

Northwestern, together with the University of Illinois campuses in Chicago and Urbana-Champaign, is now more involved in the leadership of Argonne, which is operated by the University of Chicago. President Bienen and Vice President Moore serve on Argonne’s board of governors, and Moore also serves on the science policy council. The universities are supporting joint appointments as well as scientific institutes at the laboratory.

In addition to these new partnerships, Northwestern was instrumental in Children’s Memorial Hospital’s decision this year to build a new facility one block west of the Feinberg School. The move will add the pediatric hospital to an academic medical center in downtown Chicago that includes the Feinberg School, Northwestern Memorial Hospital and the Rehabilitation Institute of Chicago. All of these hospitals are teaching facilities for the University.

These developments are certain to fuel the research activities at Northwestern in ways no one can predict, increasing the likelihood that innovative solutions to health care problems will emerge from the University’s labs. But progress doesn’t happen overnight.

A good example is pregabalin, a small organic molecule first synthesized by Richard Silverman, John Evans Professor of Chemistry and professor of biochemistry, molecular biology and cell biology, in 1989. The drug, which is used for nerve pain associated with diabetes and shingles and for epileptic seizures, became available in the United States only last year. (Pregabalin is marketed by Pfizer Inc. under the name Lyrica.)

Advances in medicine rely on research and the successful translation of that research into something that benefits the health of patients, whether it be pharmaceutical products, diagnostics or surgical interventions. This can be a very long road, requiring patents, additional research and testing, commercialization, Food and Drug Administration approval and human studies. But it’s a road that discoveries must travel.

“Research is a long-term investment,” says Kessler. “Sometimes people forget the difference science and research have made on medicine — the impact has been huge. I’ve dedicated my life to regenerating the nervous system and hope to make a contribution. All scientists want to change the world.”

Editor’s note:The research highlighted in this article represents only a small fraction of the work going on at Northwestern.

Megan Fellman is a senior editor in the Department of University Relations. She covers the sciences and engineering for the media relations group.